There remain clear clinical and public health needs to improve the early detection of breast, colorectal, and ovary cancers. For breast and colorectal cancers effective, widely used screening tests exist, but for breast cancer there remain issues with respect to optimizing mammography's use and performance, and for colorectal cancer both limited access to and the invasiveness of colonoscopy are barriers to its wider use. Ovary cancer is less common but highly lethal, and no clinically useful tests for its early detection are currently available. Through the current breast and ovary cancer EDRN Clinical Validation Center (CVC) led by Dr. Li and the current colorectal cancer EDRN Biomarker Development Laboratory (BDL) led by Dr. Lampe, we have discovered and validated promising sets of candidate early detection biomarkers for each of these three cancers that now warrant further Phase 2 and Phase 3 validation. We propose the following three projects: Project 1: Phase 3 validation of early detection biomarkers for ER+ breast cancer: Nine candidate biomarkers that have been preliminarily validated in preclinical samples will be assessed in an independent set of preclinical samples. Their intended clinical applications are to: 1. Inform timing of a subsequent mammogram in women with a negative screening mammogram; 2. Inform continuation of mammographic screening among women 75-79 years; 3. Prioritize women who should be screened with mammography in areas with limited resources. Project 2: Phase 3 validation of early detection biomarkers for colorectal cancer: We will validate five biomarkers that have been preliminarily validated in multiple sets of samples with performance that meets or exceeds those of existing fecal tests. Our intended clinical applications are to: 1. Identify people unwilling to undergo or with no access to colonoscopy who should be prioritized for colonoscopy (improve/replace existing FIT and Cologuard tests); 2. Among symptomatic patients identify those who have a very low risk of cancer and can avoid colonoscopy. Project 3: Phase 2 and 3 validation of auto- antibodies (AAb) as early detection biomarkers for serous ovarian cancer (SOC): Our overall goal is to combine novel AAb markers with currently available tests in a two-stage screening strategy with the potential to reduce ovarian cancer mortality. Our intended clinical applications are: 1. Use AAbs in conjunction with CA125 as a first line screening test; 2. Use AAbs in conjunction with HE4 for cancer early detection in women with rising CA125. In addition, we will serve as an EDRN collaborative resource providing biospecimens and expertise to support high quality PRoBE compliant EDRN discovery and validation studies across cancer types. With the combined expertise of our multidisciplinary team of investigators, this CVC will both lead well- justified, rigorously designed validation studies and provide abundant resources to EDRN. Given the strength of our biomarker candidates, the sets of biospecimens that will be used, the study designs employed, and the clearly delineated clinical applications proposed, we anticipate that this work will yield near-ter clinical impact.